Piperazine derivatives

ABSTRACT

A compound of the formula                    
     or the pharmaceutically acceptable salt thereof; wherein a, b, c, d, e, j, R 1 , R 2 , R 3 , and R 4  are as defined herein and are useful to treat inflammation and other immune disorders.

BACKGROUND OF THE INVENTION

The present invention relates to novel piperazine derivatives, methodsof use and pharmaceutical compositions containing them.

The compounds of the invention are potent and selective inhibitors ofchemokine binding to its receptor CCR1 found on inflammatory andimmunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1receptor is also sometimes referred to as the CC-CKR1 receptor. Thesecompounds also inhibit MIP-1α (and the related chemokines shown tointeract with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1cells and human leukocytes and are potentially useful for the treatmentor prevention of autoimmune diseases (such as rheumatoid arthritis, typeI diabetes (recent onset), lupus, inflammatory bowel disease, opticneuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica,uveitis, and vasculitis), acute and chronic inflammatory conditions(such as osteoarthritis, adult Respiratory Distress Syndrome,Respiratory Distress Syndrome of infancy, ischemia reperfusion injury,and glomerulonephritis), allergic conditions (such as asthma and atopicdermatitis), infection associated with inflammation (such as viralinflammation (including influenza and hepatitis) and Guillian-Barre),chronic bronchitis, xeno-transplantation, transplantation tissuerejection (chronic and acute), organ transplant rejection (chronic andacute), atherosclerosis, restenosis, HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis) and sequelae associated with certain cancers such asmultiple myeloma. Compounds in this series may also limit the productionof cytokines at inflammatory sites, including but not limited to TNF andIL-1, as a consequence of decreasing cell infiltration, providingbenefit for diseases linked to TNF and IL-1, including congestive heartfailure, pulmonary emphysema or dyspnea associated therewith, emphysema;HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses(Herpes zoster and Herpes simplex). They may also provide benefit forthe sequelae associated with infection where such infection inducesproduction of detrimental inflammatory cytokines such as TNF e.g, fungalmeningitis, joint tissue damage, hyperplasia, pannus formation and boneresorption, psoriatic arthritis, hepatic failure, bacterial meningitis,Kawasaki syndrome, myocardial infarction, acute liver failure, lymedisease, septic shock, cancer, trauma, and malaria.

MIP-1α and RANTES are soluble chemotactic peptides (chemokines) whichare produced by inflammatory cells, in particular CD8+ lymphocytes,polymorphonuclear leukocytes (PMNs) and macrophages, J. Biol. Chem., 270(30) 29671-29675 (1995). These chemokines act by inducing the migrationand activation of key inflammatory and immunomodulatory cells. Elevatedlevels of chemokines have been found in the synovial fluid of rheumatoidarthritis patients, chronic and acute rejecting tissue from transplantpatients and in the nasal secretions of allergic rhinitis patientsfollowing allergen exposure (Teran, et al., J. Immunol., 1806-1812(1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)).Antibodies which interfere with the chemokine/receptor interaction byneutralizing MIP1α or gene disruption have provided direct evidence forthe role of MIP-1α and RANTES in disease by limiting the recruitment ofmonocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704(1994) and Cook et al., Science, 269, 1583 (1995)). Together this datademonstrates that CCR1 receptor antagonists would be an effectivetreatment of several immune based diseases. The compounds describedwithin are potent and selective antagonists of the CCR1 receptor.

SUMMARY OF THE INVENTION

The present invention also relates to a compound of the formula

or the pharmaceutically acceptable salt thereof; wherein

a is 1, 2, 3, 4 or 5;

b is 0, 1, 2, 3 or 4;

c is 0 or 1;

d is 1, 2, 3, 4 or 5;

e is 0 or 1;

j is 1, 2, 3, or 4;

X is C(O), C(S) or CH₂;

Y is CH₂, or if e is 0, Y is CHR⁸ wherein R⁸ is hydrogen, (C₆-C₁₀)arylor NR⁹R¹⁰;

Z is oxygen, NR⁹ or CR¹¹R¹²;

each R¹ is independently selected from hydrogen, hydroxy,hydroxysulfonyl, halo, (C₁-C₆)alkyl, mercapto, mercapto(C₁-C₆)alkyl,(C₁-C₆)alkylthio, (C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsufonyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,halo(C₁-C₆)alkyl, trifluoromethyl, formyl, formyl(C₁-C₆)alkyl, nitro,nitroso, cyano, (C₆-C₁₀)aryl(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,trifluoromethoxy, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl(C₁-C₆)alkyl,hydroxy(C₃-C₇)cycloalkyl(C₁-C₆)alkyl, (C₃-C₇)cycloalkylamino,(C₃-C₇)cycloalkylamino(C₁-C₆)alkyl,((C₃-C₇)cycloalkyl)((C₁-C₆)alkyl)amino,((C₃-C₇)cycloalkyl(C₁-C₆)alkyl)amino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,(C₂-C₇)alkenyl, (C₂-C₇)alkynyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₂-C₆)alkenyl, hydroxy(C₁-C₆)alkyl,hydroxy(C₆-C₁₀)aryl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkylthio(C₁-C₆)alkyl,hydroxy(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₆-C₁₀)aryloxy(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylamino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₆-C₁₀)acylamino(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkoxycarbonyl)(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,

, (C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonyl, (C₆-C₁₀)arylcarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl,(C₆-C₁₀)aryl(C₁-C₆)alkycarbonyl(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonyloxy(C₁-C₆)alkyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂aminocarbonyl,(C₆-C₁₀)arylaminocarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)arylaminocarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, amidino, guanidino, ureido,(C₁-C₆)alkylureido, ((C₁-C₆)alkyl)₂ureido, ureido(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl and (C₂-C₉)heteroaryl(C₁-C₆)alkyl;

each R² and R³ are independently selected from oxo, halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylamino(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkylamino(C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₂-C₆)alkenyl, H—C(O)—, H—C(O)—(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkynyl,hydroxy(C₆-C₁₀)aryl(C₁-C₆)alkyl, hydroxy(C₃-C₈)cycloalkyl(C₁-C₆)alkyl,thio(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl,halo(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C¹-C₆)alkoxy(C₆-C₁₀)aryl(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₆-C₁₀)aryloxy(C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkylthio(C₁-C₆)alkyl,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, (C₆-C₁₀)arylamino(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl, azido(C₁-C₆)alkyl,aminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C¹-C₆)alkoxycarbonylamino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₆-C₁₀)aryloxy(C₁-C₆)alkylcarbonyloxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonyloxy(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonyloxy(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl, carboxy,(C₁-C₆)alkoxycarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂aminocarbonyl,(C₆-C₁₀)arylaminocarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)arylaminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonyl,(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl, (C₂-C₉)heteroaryl(C₁-C₆)alkyl orR¹⁴R¹⁵N(C₁-C₆)alkyl wherein R¹⁴ and R¹⁵ are each independently(C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl;

R⁴ is (R⁵)_(f)(R⁶)_(g)(C₆-C₁₀)aryl, (R⁵)_(f)(R⁶)_(g)(C₃-C₁₀)cycloalkyl,(R⁵)_(f)(R⁷)_(h)(C₂-C₉)heteroaryl, or(R⁵)_(f)(R⁷)_(h)(C₂-C₉)heterocycloalkyl,

wherein f is 1, 2, 3 or 4;

g and h are each independently 0, 1, 2 or 3;

R⁵ is one to three groups independently selected from(C₂-C₉)heterocycloalkylcarbonyl, (C₂-C₉)heteroarylcarbonyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminocarbonyl,ureido(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylureido(C₁-C₆)alkylaminocarbonyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylaminocarbonyl,halo(C₁-C₆)alkylaminocarbonyl, aminosulfonyl(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylaminosulfonyl(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylcarbonylamino,cyanoguanidino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylcarbonylamino,aminocarbonyl(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcarbonylamino,aminosulfonyl(C₁-C₆)alkylcarbonylamino, hydroxy(C₁-C₆)alkylureido,amino(C₁-C₆)alkylureido, (C₁-C₆)alkylamino(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylureido,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylureido,(C₂-C₉)heteroaryl(C₁-C₆)alkylureido, aminosulfonyl(C₁-C₆)alkylureido,aminocarbonyl(C₁-C₆)alkylureido,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylureido,acetylamino(C₁-C₆)alkylureido,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylureido,halo(C₁-C₆)alkylsulfonylamino, amino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino,acetylamino(C₁-C₆)alkylsulfonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino,ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylsulfonylamino,aminocarbonyl(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino, aminosulfonylamino,(C₁-C₆)alkylaminosulfonylamino, ((C₁-C₆)alkyl)₂aminosulfonylamino,aminocarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino, (C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂cyanoguanidino, (C₂-C₉)heterocycloalkylcyanoguanidino,(C₂-C₉)heteroarylcyanoguanidino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcyanoguanidino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcyanoguanidino,amino(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylamino(C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylcyanoguanidino,aminocarbonyl(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcyanoguanidino,aminocarbonyl(C₁-C₆)alkylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino,aminosulfonyl(C₁-C₆)alkylamino, (C₂-C₉)heteroaryl(C₁-C₆)alkylamino,acetylamino(C₁-C₆)alkylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkyl,cyano(C₁-C₆)alkylaminoalkyl, aminocarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkyl,acetylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylamino(C₁-C₆)alkyl,aminocarbonyloxy(C₁-C₆)alkylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,aminosulfonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,cyano(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,amino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylureido(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylureido(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylureido(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylureido(C₁-C₆)alkyl,halo(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,amino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,acetylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂(cyanoguanidino)(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,aminosulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminosulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminosulfonylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkyl, (C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(cyanoguanidino)amino,(C₂-C₉)heteroaryl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,amino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,aminosulfonyl, (C₁-C₆)alkylaminosulfonyl, ((C₁-C₆)alkyl)₂aminosulfonyl,(C₂-C₉)heterocycloalkylsulfonyl, amino(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylamino(C₁-C₆)alkylaminosulfonyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroarylaminosulfonyl, hydroxy(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkoxy(C₁-C₆)alkylaminosulfonyl, ureido(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylureido(C₁-C₆)alkylaminosulfonyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylaminosulfonyl,aminocarbonyl(C₁-C₆)alkylaminosulfonyl,cyanoguanidino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heterocycloalkylaminosulfonyl, R⁶ is one to three groupsindependently selected from hydrogen, hydroxy, hydroxysulfonyl, halo,(C₁-C₆)alkyl, mercapto, mercapto(C₁-C₆)alkyl, (C₁-C₆)alkylthio,(C₁-C₆)alkylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)alkylthio(C₁-C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, halo(C₁-C₆)alkyl, trifluoro(C₁-C₆)alkyl, formyl,formyl(C₁-C₆)alkyl, nitro, nitroso, cyano, (C₆-C₁₀)aryl(C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, trifluoro(C₁-C₆)alkoxy, amino(C₁-C₆)alkoxy,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl,hydroxy(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl, (C₃-C₁₀)cycloalkylamino,(C₃-C₁₀)cycloalkylamino(C₁-C₆)alkyl, cyano(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₂-C₆)alkenyl, hydroxy(C₁-C₆)alkyl, (hydroxy)(C₆-C₁₀)aryl(C₁-C₆)alkyl, ((C₁-C₆)alkylamino)(C₆-C₁₀)aryl(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkylthio(C₁-C₆)alkyl, hydroxy(C₂-C₆)alkenyl,hydroxy(C₂-C₆)alkenyl, hydroxy(C₂-C₆)alkynyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₆-C₁₀)aryl(C₁-C₆)alkyl, aryloxy(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylamino,amino(C₁-C₆)alkylamino, (C₂-C₉)heterocycloalkylamino,(C₂-C₉)heteroarylamino, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl)amino,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxycarbonylamino,(C₂-C₆)alkenylcarbonylamino, (C₃-C₁₀)cycloalkylcarbonylamino,(C₆-C₁₀)arylcarbonylamino, (C₂-C₉)heterocycloalkylcarbonylamino,halo(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxy(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,((C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino, (C₁-C₆)alkylsulfonylamino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylamino(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkylsulfonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl,((C₆-C₁₀)arylsulfonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkylamino(C₁-C₆)alkyl,(C₂-C₉)heteroarylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylcarbonyl,(C₆-C₁₀)arylcarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl,hydroxy(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonyloxy(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyloxy(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl, (C₆-C₁₀)arylcarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂aminocarbonyl,(C₆-C₁₀)arylaminocarbony), (C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl,(aminocarbonyl(C₁-C₆)alkylaminocarbonyl,((C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylaminocarbonyl,((C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylaminocarbonyl,(amino(C₁-C₆)alkyl)aminocarbonyl, (hydroxy(C₁-C₆)alkylaminocarbonyl,aminocarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)arylaminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl, amidino,hydroxyamidino, guanidino, ureido, (C₁-C₆)alkylureido,(C₆-C₁₀)arylureido, ((C₆-C₁₀)aryl)₂ureido,(C₆-C₁₀)aryl(C₁-C₆)alkylureido, halo(C₁-C₆)alkylureido,((C₁-C₆)alkyl)((C₆-C₁₀)aryl)ureido, ((C₁-C₆)alkyl)₂ureido,halo(C₁-C₆)alkylcarbonylureido, ureido(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkyl,(C₆-C₁₀)arylureido(C₁-C₆)alkyl, (C₆-C₁₀)aryl)₂ureido(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylureido(C₁-C₆)alkyl,halo(C₁-C₆)alkylureido(C₁-C₆)alkyl,(halo(C₁-C₆)alkyl)((C₁-C₆)alkyl)ureido(C₁-C₆)alkyl,((C₁-C₆)alkoxycarbonyl (C₁-C₆)alkyl)ureido(C₁-C₆)alkyl, glycinamido,(C₁-C₆)alkylglycinamido, aminocarbonylglycinamido,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonylglycinamido,(aminocarbonyl)((C₁-C₆)alkyl)glycinamido,((C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)glycinamido,((C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylcarbonyl)glycinamido,(C₆-C₁₀)arylcarbonylglycinamido,((C₆-C₁₀)arylcarbonyl)((C₁-C₆)alkyl)glycinamido,((C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl)glycinamido,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl)((C₁-C₆)alkyl)glycinamido,(C₆-C₁₀)arylaminocarbonylglycinamido,((C₆-C₁₀)arylaminocarbonyl)((C₁-C₆)alkyl)glycinamido,glycinamido(C₁-C₆)alkyl, alaninamido, (C₁-C₆)alkylalaninamido,alaninamido(C₁-C₆)alkyl, (C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkyl and (C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl;

R⁷ is one to three groups independently selected from hydrogen, hydroxy,halo, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, formyl, nitro,cyano, halo(C₁-C₆)alkoxy, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylamino,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxycarbonylamino,(C₂-C₆)alkenylcarbonylamino, cycloalkylcarbonylamino,(C₆-C₁₀)arylcarbonylamino, halo(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,((C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino, (C₁-C₆)alkylsulfonylamino,amino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylcarbonyl,(C₆-C₁₀)arylcarbonyl, (C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂aminocarbonyl,(C₆-C₁₀)arylaminocarbonyl, aminocarbonyl(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)arylaminocarbonyl(C₁-C₆)alkyl, guanidino, ureido,(C₁-C₆)alkylureido, ureido(C₁-C₆)alkyl, (C₁-C₆)alkylureido(C₁-C₆)alkyl,and glycinamido;

R⁹ and R¹⁰ are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl(C₁-C₆)alkyl, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂aminocarbonyl and(C₁-C₆)alkoxycarbonyl; and

R¹¹ and R¹² are each independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, amino,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylcarbonylamino,(C₃-C₈)cycloalkylcarbonylamino,(C₃-C₈)cycloalkyl(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxycarbonylamino,(C₁-C₆)alkylsulfonylamino, (C₆-C₁₀)arylcarbonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonylamino,((C₆-C₁₀)aryl(C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkylcarbonylamino(C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroarylcarbonylamino(C₁-C₆)alkyl, (C₆-C₁₀)arylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, aminocarbonylamino,(C₁-C₆)alkylaminocarbonylamino, halo(C₁-C₆)alkylaminocarbonylamino,((C₁-C₆)alkyl)₂aminocarbonylamino, aminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonylamino(C₁-C₆)alkyl,halo(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl and (C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl.

Preferred compounds of formula I include those wherein R¹ is hydrogen,halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)alkyl,hydroxy or (C₁-C₆)alkylcarbonyloxy.

Other preferred compounds of formula I include those wherein R² and R³are each independently selected from (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,amino(C₁-C₆)alkyl, amino(C₃-C₈)cycloalkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, (C₁-C₆)alkylamino(C₃-C₈)cycloalkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkyl, (C₁-C₆)alkyureido(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkyl or (C₂-C₉)heterocycloalkyl (C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O), d is 1; Y is CH₂; e is 1; and Z is oxygen.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O); d is 2; Y is ethylene; and e is 0.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O); d is 1; Y is CH₂; e is 1; and Z is NR⁹ wherein R⁹ is hydrogenor (C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 1; Y is CH₂; e is 1; and Z is oxygen.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 2; Y is ethylene; and e is 0.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 1; Y is CH₂; e is 1, and Z is NR⁹ wherein R⁹ is hydrogen or(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O); d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is oxygen.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O); d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is CR¹¹R¹² wherein R¹¹ and R¹² are hydrogen.

Other preferred compounds of formula I include those wherein c is 1; Xis C(O); d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is NR⁹ wherein R⁹ is hydrogen or (C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is oxygen.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is CR¹¹R¹² wherein R¹¹ and R¹² are hydrogen.

Other preferred compounds of formula I include those wherein c is 1; Xis CH₂; d is 1; Y is CHR⁸ wherein R⁸ is NR⁹R¹⁰; R⁹ and R¹⁰ are eachindependently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)alkylcarbonyl; e is 1;and Z is NR⁹ wherein R⁹ is hydrogen or (C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁴ is(R⁵)_(f)(R⁶)_(g)(C₆-C₁₀)aryl or (R⁵)_(f)(R⁷)_(h)(C₂-C₉)heteroarylwherein f, g and h are independently 1 or 2.

Other preferred compounds of formula I include those wherein R⁵ is(C₂-C₉)heterocycloalkylcarbonyl, (C₂-C₉)heteroarylcarbonyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminocarbonyl,ureido(C₁-C₆)alkylaminocarbonyl,(C₁-C₆)alkylureido(C₁-C₆)alkylaminocarbonyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylaminocarbonyl,aminosulfonyl(C₁-C₆)alkylaminocarbonyl or(C₁-C₆)alkylaminosulfonyl(C₁-C₆)alkylaminocarbonyl.

Other preferred compounds of formula I include those wherein R⁵ is(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylcarbonylamino,cyanoguanidino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylcarbonylamino,aminocarbonyl(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcarbonylamino, oraminosulfonyl(C₁-C₆)alkylcarbonylamino.

Other preferred compounds of formula I include those wherein R⁵ isamino(C₁-C₆)alkylureido, (C₁-C₆)alkylamino(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylureido,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylureido,(C₂-C₉)heteroaryl(C₁-C₆)alkylureido, aminosulfonyl(C₁-C₆)alkylureido,aminocarbonyl(C₁-C₆)alkylureido,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylureido,acetylamino(C₁-C₆)alkylureido,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylureido.

Other preferred compounds of formula I include those wherein R⁵ isamino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino,acetylamino(C₁-C₆)alkylsulfonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino,ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylsulfonylamino,aminocarbonyl(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino, aminosulfonylamino,(C₁-C₆)alkylaminosulfonylamino, ((C₁-C₆)alkyl)₂aminosulfonylamino,aminocarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino or(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino.

Other preferred compounds of formula I include those wherein R⁵ iscyanoguanidino, (C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂cyanoguanidino, (C₂-C₉)heterocycloalkylcyanoguanidino,(C₂-C₉)heteroarylcyanoguanidino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcyanoguanidino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcyanoguanidino,amino(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylamino(C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylcyanoguanidino,aminocarbonyl(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcyanoguanidino or((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcyanoguanidino.

Other preferred compounds of formula I include those wherein R⁵ isaminocarbonyl(C₁-C₆)alkylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino,aminosulfonyl(C₁-C₆)alkylamino, (C₂-C₉)heteroaryl(C₁-C₆)alkylamino,acetylamino(C₁-C₆)alkylamino or(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino.

Other preferred compounds of formula I include those wherein R⁵ iscyano(C₁-C₆)alkylaminoalkyl oraminocarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ isacetylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylamino(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylamino(C₁-C₆)alkyl oraminocarbonyloxy(C₁-C₆)alkylamino(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ isacetylamino(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,aminosulfonyl(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl orcyano(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ isamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkylaminocarbonyl amino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl amino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylureido(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylureido(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylureido(C₁-C₆)alkyl orcyanoguanidino(C₁-C₆)alkylureido(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ isamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,acetylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,ureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,cyanoguanidino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂(cyanoguanidino)(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,aminosulfonylamino(C₁-C₆)alkyl,(C₁-C₆)alkylaminosulfonylamino(C₁-C₆)alkyl or((C₁-C₆)alkyl)₂aminosulfonylamino(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ iscyanoguanidino(C₁-C₆)alkyl, (C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₂-C₉)heteroaryl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,amino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl or((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkyl.

Other preferred compounds of formula I include those wherein R⁵ is(C₂-C₉)heterocycloalkylsulfonyl, amino(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylamino(C₁-C₆)alkylaminosulfonyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroarylaminosulfonyl, ureido(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylureido(C₁-C₆)alkylaminosulfonyl,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminosulfonyl,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylaminosulfonyl,aminocarbonyl(C₁-C₆)alkylaminosulfonyl,cyanoguanidino(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminosulfonyl,(C₂-C₉)heterocycloalkylaminosulfonyl, Other preferred compounds offormula I include those wherein R⁵ is halo(C₁-C₆)alkylaminocarbonyl,hydroxy(C₁-C₆)alkylureido, halo(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkyl,halo(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, ((C₁-C₆)alkyl)₂aminosulfonyl,hydroxy(C₁-C₆)alkylaminosulfonyl, and(C₁-C₆)alkoxy(C₁-C₆)alkylaminosulfonyl.

Other preferred compounds of formula I include those wherein R⁶ and R⁷are each independently halo, halo(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy,aminocarbonyl, cyano, ureido, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino or glycinamino.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

The present invention also relates to compounds of formula I wherein anyof the hydrogens may optionally be replaced by deuterium.

Unless otherwise indicated, the alkyl, alkenyl and alkynyl groupsreferred to herein, as well as the alkyl moieties of other groupsreferred to herein (e.g., alkoxy), may be linear or branched, and theymay also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl) or be linear or branched and contain cyclicmoieties. Unless otherwise indicated, halogen includes fluorine,chlorine, bromine, and iodine.

(C₃-C₁₀)Cycloalkyl when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl etc.

(C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, or chromanyl.

(C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl,pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl,tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, or benzoxazinyl.

Aryl when used herein refers to phenyl or naphthyl.

The term “ureido”, as used herein, refers to an “amino-carbonyl-amino”moiety.

The term “acetyl”, as used herein, refers to an “alkyl-carbonyl” moietywherein alkyl is defined as above.

The term “cyanoguanidino”, as used herein, refers to a functional grouphaving the following formula

The term “(C₂-C₉)heterocycloalkyl(C═N—CN)amino”, as used herein refersto a functional group having the following formula

wherein “HET” refers to a (C₂-C₉)heterocyloalkyl or (C₂-C₉)heteroarylgroup and the nitrogen of said group is the place of attachment.

The term “mercapto”, as used herein, refers to a “HS-” moeity.

The compounds of this invention include all conformational isomers(e.g., cis and trans isomers) and all optical isomers of compounds ofthe formula I (e.g., enantiomers and diastereomers), as well as racemic,diastereomeric and other mixtures of such isomers.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases, rheumatoid arthritis, recent onset type I diabetes, lupus,inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute andchronic inflammatory conditions, osteoarthritis, adult RespiratoryDistress Syndrome, Respiratory Distress Syndrome of infancy, ischemiareperfusion injury, glomerulonephritis, allergic conditions, asthma,atopic dermatitis, infection associated with inflammation, viralinflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis, HIV infectivity, granulomatous diseases,sarcoidosis, leprosy and tuberculosis and sequelae associated withcertain cancers such as multiple myeloma. Compounds in this series mayalso limit the production of cytokines at inflammatory sites, includingbut not limited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g, fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprising anamount of a compound of the formula I or a pharmaceutically acceptablesalt thereof effective in treating or preventing such disorder orcondition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by inhibiting chemokine binding to the receptor CCR1 in amammal, preferably a human, comprising an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof, effective intreating or preventing such disorder or condition and a pharmaceuticallyacceptable carrier Examples of such disorders and conditions are thoseenumerated in the preceding paragraph.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases,rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatorybowel disease, optic neuritis, psoriasis, multiple sclerosis,polymyalgia rheumatica, uveitis, vasculitis, acute and chronicinflammatory conditions, osteoarthritis, adult Respiratory DistressSyndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusioninjury, glomerulonephritis, allergic conditions, asthma, atopicdermatitis, infection associated with inflammation, viral inflammation,influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis, HIV infectivity, granulomatous diseases,sarcoidosis, leprosy and tuberculosis and sequelae associated withcertain cancers such as multiple myeloma. Compounds in this series mayalso limit the production of cytokines at inflammatory sites, includingbut not limited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g, fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment or prevention anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that is effective in treating or preventing such disorderor condition.

The present invention also relates to a method for treating orpreventing a disorder or condition that can be treated or prevented byantagonizing the CCR1 receptor in a mammal, preferably a human,comprising administering to a mammal in need of such treatment orprevention an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingor preventing such disorder or condition.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition selected from autoimmunediseases, rheumatoid arthritis, recent onset type I diabetes, lupus,inflammatory bowel disease, optic neuritis, psoriasis, multiplesclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute andchronic inflammatory conditions, osteoarthritis, adult RespiratoryDistress Syndrome, Respiratory Distress Syndrome of infancy, ischemiareperfusion injury, glomerulonephritis, allergic conditions, asthma,atopic dermatitis, infection associated with inflammation, viralinflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis, HIV infectivity, granulomatous diseases,sarcoidosis, leprosy and tuberculosis and sequelae associated withcertain cancers such as multiple myeloma. Compounds in this series mayalso limit the production of cytokines at inflammatory sites, includingbut not limited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g, fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprising a CCR1receptor antagonizing effective amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention also relates to a pharmaceutical composition fortreating or preventing a disorder or condition that can be treated orprevented by antagonizing the CCR1 receptor in a mammal, preferably ahuman, comprising a CCR1 receptor antagonizing effective amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for treating orpreventing a disorder or condition selected from autoimmune diseases,rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatorybowel disease, optic neuritis, psoriasis, multiple sclerosis,polymyalgia rheumatica, uveitis, vasculitis, acute and chronicinflammatory conditions, osteoarthritis, adult Respiratory DistressSyndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusioninjury, glomerulonephritis, allergic conditions, asthma, atopicdermatitis, infection associated with inflammation, viral inflammation,influenza, hepatitis, Guillian-Barre, chronic bronchitis,xeno-transplantation, chronic and acute transplantation tissuerejection, chronic and acute organ transplant rejection,atherosclerosis, restenosis, HIV infectivity, granulomatous diseases,sarcoidosis, leprosy and tuberculosis and sequelae associated withcertain cancers such as multiple myeloma. Compounds in this series mayalso limit the production of cytokines at inflammatory sites, includingbut not limited to TNF and IL-1, as a consequence of decreasing cellinfiltration, providing benefit for diseases linked to TNF and IL-1,including congestive heart failure, pulmonary emphysema or dyspneaassociated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus(CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).They may also provide benefit for the sequelae associated with infectionwhere such infection induces production of detrimental inflammatorycytokines such as TNF e.g, fungal meningitis, joint tissue damage,hyperplasia, pannus formation and bone resorption, psoriatic arthritis,hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardialinfarction, acute liver failure, lyme disease, septic shock, cancer,trauma, and malaria in a mammal, preferably a human, comprisingadministering to a mammal in need of such treatment or prevention a CCR1receptor antagonizing effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated a, b, c,d, e, j, R¹, R², R³ and R⁴ in the reaction Schemes and the discussionthat follow are defined as above.

R¹⁶ and R¹⁷ together with the nitrogen to which they are attached isselected from the group consisting of amino,amino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylcarbonylamino((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylcarbonylamino,acetylamino(C₁-C₆)alkylcarbonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylcarbonylamino,cyanoguanidino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylcarbonylamino,aminocarbonyl(C₁-C₆)alkylcarbonylamino,aminocarbonylamino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylaminocarbonylamino(C₁-C₆)alkylcarbonylamino((C₁-C₆)alkyl)₂aminocarbonylamino(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcarbonylamino,aminosulfonyl(C₁-C₆)alkylcarbonylamino, hydroxy(C₁-C₆)alkylureido,(amino(C₁-C₆)alkylureido, (C₁-C₆)alkylamino(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylureido,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylureido,(C₂-C₉)heteroaryl(C₁-C₆)alkylureido, aminosulfonyl(C₁-C₆)alkylureido,aminocarbonyl(C₁-C₆)alkylureido,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylureido,acetylamino(C₁-C₆)alkylureido,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylureido,carboxy(C₁-C₆)alkylureido, halo(C₁-C₆)alkylsulfonylamino,amino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino,acetylamino(C₁-C₆)alkylsulfonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino,ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylsulfonylamino,aminocarbonyl(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino, aminosulfonylamino,(C₁-C₆)alkylaminosulfonylamino, ((C₁-C₆)alkyl)₂aminosulfonylamino,aminocarbonyl(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino, (C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂cyanoguanidino, (C₂-C₉)heterocycloalkylcyanoguanidino,(C₂-C₉)heteroarylcyanoguanidino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylcyanoguanidino,(C₂-C₉)heteroaryl(C₁-C₆)alkylcyanoguanidino,amino(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylamino(C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylcyanoguanidino,aminocarbonyl(C₁-C₆)alkylcyanoguanidino,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcyanoguanidino,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcyanoguanidino,hydroxy(C₁-C₆)alkylamino, aminocarbonyl(C₁-C₆)alkylamino,carboxy(C₁-C₆)alkylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino,aminosulfonyl(C₁-C₆)alkylamino, (C₂-C₉)heteroaryl(C₁-C₆)alkylamino,acetylamino(C₁-C₆)alkylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylamino,amino(C₁-C₆)alkylamino, (C₂-C₉)heterocycloalkylamino,(C₂-C₉)heteroarylamino, (C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl)amino,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxycarbonylamino,(C₂-C₆)alkenylcarbonylamino, (C₃-C₁₀)cycloalkylcarbonylamino,(C₆-C₁₀)arylcarbonylamino, (C₂-C₉)heterocycloalkylcarbonylamino,halo(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkoxy(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,((C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino, (C₁-C₆)alkylsulfonylamino,(C₃-C₁₀)cycloalkylamino, ureido, (C₁-C₆)alkylureido, (C₆-C₁₀)arylureido,((C₆-C₁₀)aryl)₂ureido, (C₆-C₁₀)aryl(C₁-C₆)alkylureido,halo(C₁-C₆)alkylureido, ((C₁-C₆)alkyl)((C₆-C₁₀)aryl)ureido,((C₁-C₆)alkyl)₂ureido, halo(C₁-C₆)alkylcarbonylureido, glycinamido,(C₁-C₆)alkylglycinamido, aminocarbonylglycinamido,(C₁-C₆)alkoxy(C₁-C₆)alkylcarbonylglycinamido,(aminocarbonyl)((C₁-C₆)alkyl)glycinamido,((C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)glycinamido,((C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylcarbonyl)glycinamido,(C₆-C₁₀)arylcarbonylglycinamido,((C₆-C₁₀)arylcarbonyl)((C₁-C₆)alkyl)glycinamido,((C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl)glycinamido,(C₆-C₁₀)aryl(C₁-C₆)alkylaminocarbonyl)((C₁-C₆)alkyl)glycinamido,(C₆-C₁₀)arylaminocarbonylglycinamido and((C₆-C₁₀)arylaminocarbonyl)((C₁-C₆)alkyl)glycinamido.

R¹⁸ and R¹⁹ together with the nitrogen to which they are attached isselected from the group consisting of(C₂-C₉)heteroaryl(C₁-C₆)alkylamino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylamino, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino, ureido(C₁-C₆)alkylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylamino, halo(C₁-C₆)alkylamino,aminosulfonyl(C₁-C₆)alkylamino,(C₁-C₆)alkylaminosulfonyl(C₁-C₆)alkylamino, carboxy(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylamino, cyano(C₁-C₆)alkylamino,aminocarbonyl(C₁-C₆)alkylamino, acetylamino(C₁-C₆)alkylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylamino,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylamino,cyanoguanidino(C₁-C₆)alkylamino,(C₁-C₆)alkylcyanoguanidino(C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂cyanoguanidino(C₁-C₆)alkylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino, ureido(C₁-C₆)alkylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylamino,aminocarbonyloxy(C₁-C₆)alkylamino, acetylamino(C₁-C₆)alkylcarbonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylcarbonylamino,aminocarbonyl(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkylcarbonylamino,ureido(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylcarbonylamino,aminosulfonyl(C₁-C₆)alkylcarbonylamino,hydroxy(C₁-C₆)alkylamino(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxy(C₁-C₆)alkylamino(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino,(C₂-C₉)heteroarylcarbonylamino(C₁-C₆)alkylcarbonylamino,(C₂-C₉)heterocycloalkylcarbonylamino(C₁-C₆)alkylcarbonylamino,cyanoguanidino(C₁-C₆)alkylcarbonylamino, cyano(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylcarbonylamino(C₁-C₆)alkylamino-carbonylamino,amino(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylaminocarbonyl amino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylaminocarbonylamino,carboxy(C₁-C₆)alkylaminocarbonyl amino,aminocarbonyl(C₁-C₆)alkylaminocarbonylamino, (C₁-C₆)alkylcarbonylamino(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylaminocarbonylamino,(C₁-C₆)alkoxycarbonyl amino(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heterocycloalkyloxycarbonyl amino(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heterocycloalkyl(C₁-C₆)alkylaminocarbonylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylaminocarbonylamino,ureido(C₁-C₆)alkylureido, (C₁-C₆)alkylureido(C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylureido,cyanoguanidino(C₁-C₆)alkylureido, amino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylsulfonylamino,acetylamino(C₁-C₆)alkylsulfonylamino,(acetyl)((C₁-C₆)alkyl)amino(C₁-C₆)alkylsulfonylamino,ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylureido(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylsulfonylamino,cyanoguanidino(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkyl(cyanoguanidino)(C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkyl)₂(cyanoguanidino)(C₁-C₆)alkylsulfonylamino,aminocarbonyl(C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylsulfonylamino,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylsulfonylamino,aminosulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylaminosulfonylamino,((C₁-C₆)alkyl)₂aminosulfonylamino(C₁-C₆)alkyl, cyanoguanidino,(C₁-C₆)alkyl(cyanoguanidino), ((C₁-C₆)alkyl)₂(cyanoguanidino),(C₂-C₉)heterocycloalkyl(cyanoguanidino),(C₂-C₉)heterocycloalkyl(cyanoguanidino),(C₂-C₉)heteroaryl(cyanoguanidino),(C₂-C₉)heterocycloalkyl(C₁-C₆)alkyl(cyanoguanidino),(C₂-C₉)heteroaryl(C₁-C₆)alkyl(cyanoguanidino),amino(C₁-C₆)alkyl(cyanoguanidino),(C₁-C₆)alkylamino(C₁-C₆)alkyl(cyanoguanidino),((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl(cyanoguanidino),aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino),(C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkyl(cyanoguanidino),((C₁-C₆)alkyl)₂aminocarbonyl(C₁-C₆)alkyl(cyanoguanidino),(C₂-C₉)heterocycloalkyl, amino(C₁-C₆)alkylamino,(C₁-C₆)alkylamino(C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkylamino, (C₂-C₉)heteroarylamino,ureido(C₁-C₆)alkylamino, (C₁-C₆)alkylureido(C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂ureido(C₁-C₆)alkylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkylamino,(C₁-C₆)alkoxycarbonylamino(C₁-C₆)alkylamino,(C₂-C₉)heterocycloalkyloxycarbonylamino(C₁-C₆)alkylamino,(C₂-C₉)heteroaryloxycarbonylamino(C₁-C₆)alkylamino,aminocarbonyl(C₁-C₆)alkylamino, cyanoguanidino(C₁-C₆)alkylamino,(C₂-C₉)heteroaryl(C₁-C₆)alkylamino, (C₂-C₉)heterocycloalkylamino,(C₁-C₆)alkylcarbonylamino, halo(C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkoxycarbonylamino, ureido, (C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂ureido, amino, (C₁-C₆)alkylamino,(C₃-C₁₀)cycloalkylamino, ((C₁-C₆)alkyl)₂amino, hydroxy(C₁-C₆)alkylamino,(C₆-C₁₀)arylamino, (C₆-C₁₀)aryl(C₁-C₆)alkylamino,(C₁-C₆)alkylcarbonylamino, (C₆-C₁₀)arylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl)amino, (C₁-C₆)alkoxycarbonylamino,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkoxycarbonyl)((C₁-C₆)alkyl)amino, (C₁-C₆)alkylsulfonylamino,((C₁-C₆)alkylsulfonyl)((C₁-C₆)alkyl)amino, (C₆-C₁₀)arylsulfonylamino,((C₆-C₁₀)arylsulfonyl)((C₁-C₆)alkyl)amino, (C₂-C₉)heterocycloalkylamino,(C₂-C₉)heteroarylamino, halo(C₁-C₆)alkylamino, (C₆-C₁₀)arylamino,(C₆-C₁₀)aryl(C₁-C₆)alkylamino, (aminocarbonyl(C₁-C₆)alkylamino,((C₁-C₆)alkylaminocarbonyl(C₁-C₆)alkylamino, (carboxy(C₁-C₆)alkyl)amino,((C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylamino, (amino(C₁-C₆)alkyl)amino,(hydroxy(C₁-C₆)alkylamino, ureido, (C₁-C₆)alkylureido,((C₁-C₆)alkyl)₂ureido, (C₆-C₁₀)arylureido, (C₆-C₁₀)aryl)₂ureido,(C₆-C₁₀)aryl(C₁-C₆)alkylureido, halo(C₁-C₆)alkylureido,(halo(C₁-C₆)alkyl)((C₁-C₆)alkyl)ureido,((C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl)ureido, and glycinamido.

In reaction 1 of Preparation A, the compound of formula XXXV, wherein bis 0, 1 or 2, is converted to the corresponding compound of formulaXXXIV by reacting XXXV with an ethyldiamine compound of the formula,(R³)_(j)-ethyldiamine, in the presence of an aprotic solvent, such asdiethylether. The reaction mixture is heated to reflux for a time periodbetween about 1 hour to about 12 hours.

In reaction 2 of Preparation A, the compound of formula XXXIV isconverted to the corresponding compound of formula XXXIII by reducingXXXIV with a reducing agent, such as sodium borohydride, in a refluxingprotic solvent, such as ethanol.

In reaction 3 of Preparation A, the compound of formula XXXIII isconverted to the corresponding compound of formula XXX by reactingXXXIII with a benzaldehyde compound of the formula

in the presence of a base, such as triethylamine, and a reducing agent,such as sodium triacetoxyborohydride, in an aprotic solvent, such as1,2-dichloroethane. The reaction mixture is stirred at room temperaturefor a time period between about 1 hour to about 4 hours, preferablyabout 2 hours.

In reaction 1 of Preparation B, the compound of formula XXII, wherein bis 0, 1 or 2, is converted to the corresponding compound of formula XXIby reacting XXIII with a benzaldehyde compound of the formula

in the presence of a base, such as triethylamine, a reducing agent, suchas sodium borohydride and an aprotic solvent, such as1,2-dichloroethane. The reaction is stirred, at room temperature, for atime period between about 1 hour to about 4 hours, preferably about 2hours.

In reaction 2 of Preparation B, the compound of formula XXI is convertedto the corresponding compound of formula XX by first reacting a compoundof the formula

wherein j is 0, 1 or 2, with 4-methyl morpholine andisobutylchloroformate in the presence of a polar aprotic solvent, suchas tetrahydrofuran, followed by reacting the intermediate so formed withthe compound of formula XXI. The reaction mixture, so formed, is stirredovernight at room temperature.

In reaction 3 of Preparation B, the compound of formula XX is convertedto the corresponding piperizine-2,5-dione compound of formula XIX bytreating XX with trifluoroacetic acid in the presence of a polar aproticsolvent, such as methylene chloride. The reaction is stirred, at roomtemperature, for a time period between about 1 hour to about 4 hours,preferably about 2 hours.

In reaction 4 of Preparation B, the compound of formula XIX is convertedto the corresponding compound of formula XVIII by reducing XIX with areducing agent, such as lithium aluminum hydride. The reaction isconducted at a temperature between about −100° C. to about 10° C.,preferably about 0° C., for a time period between about 10 minutes toabout 90 minutes, preferably about 40 minutes.

In reaction 1 of the Preparation C, the compound of formula XXV isconverted to the corresponding compound of formula XXIV by reacting XXVwith an amine of the formula, NHR¹⁸R¹⁹, wherein R¹⁸ and R¹⁹ are eachindependently selected from hydrogen, a nitrogen containing(C₂-C₉)heterocycloalkyl or (C₂-C₉)heteroaryl group, or (C₁-C₆)alkyloptionally substituted by hydroxy, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, ((C₁-C₆)alkyl)₂carbonyl, carboxy,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkoxycarbonylamino, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, ((C₁-C₆)alkyl)₂aminosulfonyl, (C₆-C₁₀)alkoxy,(C₂-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl, (C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino, cyano, ureido,(C₁-C₆)alkylureido, ((C₁-C₆)alkyl)₂ureido, cyanoguanidino,(C₁-C₆)alkylcyanoguanidino and ((C₁-C₆)alkyl)₂cyanoguanidino, or R¹⁸ andR¹⁹ are taken together with the nitrogen to which they are attached toform a (C₂-C₉)heteroaryl or (C₂-C₉)heterocycloalkyl group, in thepresence of a polar aprotic solvent, such as methylene chloride. Thereaction mixture is stirred, at room temperature, for a time periodbetween about 1 hour to about 24 hours, preferably about 12 hours.

In reaction 2 of Preparation C, the compound of formula XXIV isconverted to the corresponding compound of formula XXIII by reactingXXIV with thiophenol in the presence of a base, such as sodium hydride,and a polar aprotic solvent, such as dimethylformamide. The reaction isheated to reflux for a time period between about 1 hour to about 10hours, preferably about 4 hours.

In reaction 3 of Preparation C, the compound of formula XXV is convertedto the corresponding compound of formula XXXVIII by reacting XXV withsodium cyanate in the presence of pyridine and a polar aprotic solvent,such as acetonitrile. The reaction is stirred, at room temperature, fora time period between about 2 hours to about 18 hours, preferably about10 hours. An amine of the formula, H₂N—C(O)—NR¹⁸R¹⁹, is then added andthe reaction mixture so formed is stirred, at room temperature, for atime period between about 2 hours to about 24 hours, preferably about 8hours

In reaction 4 of Preparation C, the compound of formula XXXVIII isconverted to the corresponding compound of formula XXXVII according tothe procedure described above in reaction 2 of Preparation C.

In reaction 1 of Scheme 1, the compound of formula XXX is converted tothe corresponding compound of formula X by reacting XXX with a compoundof the formula, A-(X)_(c)-(Y)_(d)-A, wherein A is chloro or bromo, inthe presence of a base, such as triethylamine, and a polar aproticsolvent, such as methylene chloride. The reaction is stirred at atemperature between about −10° C. to about 10° C., for a time periodbetween about 15 minutes to about 90 minutes, preferably about 30minutes.

In reaction 2 of Scheme 1, the compound of formula X is converted to thecorresponding compound of formula I by reacting X with a compound of theformula, H-(Z)_(e)-R⁴ wherein e is 1 and Z is oxygen, in the presence ofpotassium carbonate, potassium iodide and an aprotic solvent, such asbutanone. The reaction is heated to reflux for a time period betweenabout 4 hours to about 8 hours, preferably about 6 hours.

In reaction 1 of Scheme 2, the compound of formula XXX is converted tothe corresponding compound of formula I by reacting XXX with a compoundof the formula, A-(X)_(c)-(Y)_(d)-(Z)_(e)-R⁴, wherein A is chloro orbromo, in the presence of a base, such as triethylamine, and a polaraprotic solvent, such as methylene chloride. The reaction is stirred ata temperature between about −10° C. to about 10° C., for a time periodbetween about 15 minutes to about 90 minutes, preferably about 30minutes.

In reaction 1 of Scheme 3, the compound of formula X is converted to thecorresponding compound of formula XII according to the proceduredescribed above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 3, the compound of formula XII is converted tothe corresponding compound of formula XI by reacting XII with lithiumhydroxide monohydrate in the presence of methanol, tetrahydrofuran andwater. The reaction mixture is stirred overnight at room temperature.

In reaction 3 of Scheme 3, the compound of formula XI is converted tothe corresponding compound of formula II, by reacting XI with an amine,in the presence of 4-dimethylaminopyridine,1-(3-dimethylaminopropyl)-3-ethylcarbodiimine and a polar aproticsolvent, such as methylene chloride. The resulting reaction mixture isstirred overnight at room temperature.

In reaction 1 of Scheme 4, the compound of formula X is converted to thecorresponding compound of formula XV according to the proceduredescribed above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 4, the compound of formula XV is converted tothe corresponding compound of formula XIV by hydrogenating XV in thepresence of a catalyst, such as platinum on carbon, and a polar proticsolvent, such as ethanol. The reaction is carried out under a pressurebetween about 30 psi to about 40 psi, preferably about 35 psi, for atime period between about 15 minutes to about 1 hour, preferably 30minutes.

In reaction 3 of Scheme 4, for urea formation, the compound of formulaXIV is converted to the corresponding compound of formula V by firstreacting XIV with 4-nitrophenyl chloroformate in the presence of a base,such as pyridine, and a polar aprotic solvent, such as methlyenechloride, followed by reacting the intermediate so formed with an amine.The reaction mixture, so formed, is allowed to stir overnight at roomtemperature. For sulfonamide formation, the compound of formula XIV isreacted with a sulfonyl chloride compound of the formula, R¹⁶—Cl, in thepresence of a base, such as triethylamine, and a polar aprotic solvent,such as methylene chloride. The reaction is stirred overnight at ambienttemperature. For cyanoguanidine formation, the compound of formula XIVis first treated with sodium hydride in an aprotic solvent, such astetrahydrofuran, followed by reacting, the intermediate so formed withdimethyl-N-cyanodithio iminocarbonate. The reaction mixture so formed isheated to reflux overnight. The N-cyano-S-methyl-isothioureaintermediate is then reacted with an amine in the presence of a polarprotic solvent, such as methanol. For amide formation, the compound offormula XIV is reacted with an acid, such as3-tert-butoxycarbonylaminopropionic acid in the presence ofN-methylmorpholine, O-benzotriazole-1-yl-N,N,N,′N′-tetramethyluroniumhexafluorophosphate and a polar aprotic solvent, such as methylenechloride.

In reaction 1 of Scheme 5, the compound of formula X is converted to thecorresponding compound of formula XVI, wherein k is 0, 1, 2, 3 or 4,according to the procedure described above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 5, the compound of formula XVI is converted tothe corresponding compound of formula VII by reacting XVI with an amineof the formula, R¹⁶ R¹⁷N, wherein R¹⁶ and R¹⁷ are each independentlyhydrogen, a nitrogen containing (C₂-C₉)heterocycloalkyl or(C₂-C₉)heteroaryl group, or (C₁-C₆)alkyl optionally substituted byhydroxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,((C₁-C₆)alkyl)₂carbonyl, carboxy, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkoxycarbonylamino, aminosulfonyl, (C₁-C₆)alkylaminosulfonyl,((C₁-C₆)alkyl)₂aminosulfonyl, (C₆-C₁₀)alkoxy, (C₂-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₁-C₆)alkylcarbonylamino,((C₁-C₆)alkylcarbonyl)((C₁-C₆)alkyl)amino, cyano, ureido,(C₁-C₆)alkylureido, ((C₁-C₆)alkyl)₂ureido, cyanoguanidino,(C₁-C₆)alkylcyanoguanidino and ((C₁-C₆)alkyl)₂cyanoguanidino, in thepresence of a 10:1 ratio solution of dichloroethane/acetic acid. Thereaction mixture is stirred, at room temperature, for a time periodbetween about 30 minutes to about 2 hours, preferably about 1 hour. Areducing agent, such as sodium cyanoborohydride is than added to themixture and the reaction is allowed to stir overnight at roomtemperature. When R¹⁶ and/or R¹⁷ is/are hydrogen, the compound offormula VII may further be reacted according to the procedure describedabove in reaction 3 of Scheme 4, to provide ureas, sulfonamides,cyanoguanidinos, or amides.

In reaction 1 of Scheme 6, the compound of formula X is converted to thecorresponding compound of formula XXXIX according to the proceduredescribed above in reaction 2 of Scheme 1.

In reaction 2 of Scheme 6, the compound of formula X is converted to thecorresponding compound of formula XXXX according to the proceduredescribed above in reaction 2 of Scheme 1.

In reaction 1 of Scheme 7, the acid compound of formula XXXVI isconverted to the corresponding compound of formula XXXII by treatingXXXVI with thionyl chloride neat or in an aprotic solvent, at roomtemperature, for a time period between about 1 hour to about 24 hours,preferably 1 hour. The acid chloride so formed is dissolved in a polaraprotic solvent with a compound of the formula, (H₃CO)(H₃C)NH.HCl, inthe presence of an amine base, such as triethylamine. The reactionmixture is stirred, at room temperature, for a time period between about1 hour to about 48 hours, preferably about 12 hours.

In reaction 2 of Scheme 7, the amide compound of formula XXXII isconverted to the corresponding compound of formula XXXI by reactingXXXII with a (C₂-C₉)heteroaryl lithium reagent in the presence of apolar aprotic solvent at a temperature between about −100° C. to roomtemperature, preferably about −78° C. The resulting reaction mixture isstirred for a time period between about 1 hour to about 24 hours,preferably about 12 hours, at a temperature between about −78° C. toabout 50° C., preferably about 20° C.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere).

The compounds of the formula I which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula I which are also acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the herein described acidic compounds offormula I. These non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium, calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum product yields.

Compounds of the formula I and their pharmaceutically acceptable salts(hereinafter also referred to, collectively, as “the active compounds”)are potent antagonists of the CCR1 receptors. The active compounds areuseful in the treatment or prevention of autoimmune diseases (such asrheumatoid arthritis, type I diabetes (recent onset), inflammatory boweldisease, optic neuritis, psoriasis, multiple sclerosis, polymyalgiarheumatica, uveitis, and vasculitis), acute and chronic inflammatoryconditions (such as osteoarthritis, adult respiratory distress syndrome,Respiratory Distress Syndrome of infancy, ischemia reperfusion injury,and glomerulonephritis), allergic conditions (such as asthma and atopicdermatitis), infection associated with inflammation (such as viralinflammation (including influenza and hepatitis) and Guillian-Barre),chronic bronchitis, xeno-transplantation, transplantation tissuerejection, atherosclerosis, restenosis, HIV infectivity (co-receptorusage), and granulomatous diseases (including sarcoidosis, leprosy andtuberculosis).

The activity of the compounds of the invention can be assessed accordingto procedures know to those of ordinary skill in the art. Examples ofrecognized methods for determining CCR1 induced migration can be foundin Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M.,Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3.(John Wiley and Sons, NY, 1991). One specific example of how todetermine the activity of a compound for inhibiting migration isdescribed in detail below.

Chemotaxis Assay

The ability of compounds to inhibit the chemotaxis to various chemokinescan be evaluated using standard 48 or 96 well Boyden Chambers with a 5micron polycarbonate filter. All reagents and cells can be prepared instandard RPMI (BioWhitikker Inc.) tissue culture medium supplementedwith 1 mg/ml of bovine serum albumin. Briefly, MIP-1α (Peprotech, Inc.,P.O. Box 275, Rocky Hill N.J.) or other test agonists, were placed intothe lower chambers of the Boyden chamber. A polycarbonate filter wasthen applied and the upper chamber fastened. The amount of agonistchosen is that determined to give the maximal amount of chemotaxis inthis system (e.g., 1 nM for MIP-1α should be adequate).

THP-1 cells (ATCC TIB-202), primary human monocytes, or primarylymphocytes, isolated by standard techniques can then be added to theupper chambers in triplicate together with various concentrations of thetest compound. Compound dilutions can be prepared using standardserological techniques and are mixed with cells prior to adding to thechamber.

After a suitable incubation period at 37 degrees centigrade (e.g. 3.5hours for THP-1 cells, 90 minutes for primary monocytes), the chamber isremoved, the cells in the upper chamber aspirated, the upper part of thefilter wiped and the number of cells migrating can be determinedaccording to the following method.

For THP-1 cells, the chamber (a 96 well variety manufactured byNeuroprobe) can be centrifuged to push cells off the lower chamber andthe number of cells can be quantitated against a standard curve by acolor change of the dye fluorocein diacetate.

For primary human monocytes, or lymphocytes, the filter can be stainedwith Dif Quik® dye (American Scientific Products) and the number ofcells migrating can be determined microscopically.

The number of cells migrating in the presence of the compound aredivided by the number of cells migrating in control wells (without thecompound). The quotant is the % inhibition for the compound which canthen be plotted using standard graphics techniques against theconcentration of compound used. The 50% inhibition point is thendetermined using a line fit analysis for all concentrations tested. Theline fit for all data points must have an coefficient of correlation (Rsquared) of >90% to be considered a valid assay.

All of the compounds of the invention that were tested had IC₅₀ of lessthan 25 μM, in the Chemotaxis assay.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., rheumatoid arthritis) in the average adult human are preferablyarranged so that each metered dose or “puff” of aerosol contains 20 μgto 1000 μg of the compound of the invention. The overall daily dose withan aerosol will be within the range 0.1 mg to 1000 mg. Administrationmay be several times daily, for example 2, 3, 4 or 8 times, giving forexample, 1, 2 or 3 doses each time.

The active agents can be formulated for sustained delivery according tomethods well known to those of ordinary skill in the art. Examples ofsuch formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598,4,173,626, 3,119,742, and 3,492,397.

The compounds of the invention can also be utilized in combinationtherapy with, but not limited to, other therapeutic agents such as withT-cell immunosuppressant agents such as rapamycin cyclosporin A andFK-506, with steroid sparing agents such as Cellcept®, or with classicalanti-inflammatory agents (e.g. cyclooxygenase/lipoxygenase inhibitors)such as tenidap, aspirin, acetaminophen, naproxen and piroxicam.

The following Examples illustrate the preparation of the compounds ofthe present invention. NMR data are reported in parts per million (δ)and are referenced to the deuterium lock signal from the sample solvent(deuteriochloroform unless otherwise specified). Commercial reagentswere utilized without further purification. THF refers totetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatographyrefers to column chromatography performed using 32-63 mm silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard5989®, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C. Allnon-aqueous reactions were run under a nitrogen atmosphere forconvenience and to maximize yields. The names for the compounds of theinvention were created by the Autonom 2.0 PC-batch version fromBeilstein Informationssysteme GmbH (ISBN 3-89536-976-4).

EXAMPLE 1

(2R,5S)-2-[4-Chloro-2-(piperazine-1-carbonyl)-phenoxy]-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

(R)-2-(4-Fluoro-benzylamino)-propionic acid methyl ester

To a solution of (R)-2-amino-propionic acid methyl ester hydrochloride(25 g, 179 mmol) and 4-fluorobenzaldehyde (23 ml, 215 mmol) in1,2-dichloroethane (200 ml) was added triethylamine (25 ml, 179 mmol).The resulting mixture was stirred for two hours at ambient temperaturefollowed by addition of sodium acetoxyborohydride (57 g, 268 mmol) infour portions. The resulting mixture was stirred overnight at ambienttemperature. The reaction was neutralized with dilute aqueous sodiumhydroxide solution and extracted with dichloromethane (2×). The organiclayers were combined, dried over magnesium sulfate, filtered andconcentrated in vacuo. Chromatography on silica gel gave the titlecompound (34.4 g, 91% yield).

(2R,5S)-2-[(2-tert-Butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionicacid methyl ester

To a solution of (R)-2-tert-butoxycarbonylamino-propionic acid (37 g,195 mmol) in dry tetrahydrofuran (250 ml) at 0° C. was added 4-methylmorpholine (21.5 ml, 195 mmol) followed by isobutylchloroformate (25.3ml, 195 mmol). The reaction was allowed to warm to ambient temperatureand stirred for two hours. This was followed by the addition of(S)-2-(4-fluoro-benzylamino)-propionic acid methyl ester (34.4 g, 162mmol). The resulting mixture was stirred overnight at ambienttemperature. The reaction mixture was filtered through a pad of celiteand the filter cake was washed with ethyl acetate. The filtrate wasconcentrated in vacuo, diluted with ethyl acetate and washed with waterand brine. The organics were dried over magnesium sulfate, filtered andconcentrated in vacuo. Chromatography on silica gel gave the titlecompound (43.2 g, 70% yield).

(2R,5S)-1-(4-Fluoro-benzyl)-3,6-dimethyl-piperazine-2,5-dione

To a solution of(2R,5S)-2-[(2-tert-butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-amino]-propionicacid methyl ester (43 g, 382 mmol) in dichloromethane (120 ml) at 0° C.was added trifluoroacetic acid (60 ml). The reaction was allowed to warmto ambient temperature and stirred for 2 hours. The reaction was cooledto 0° C. and slowly quenched by addition of 3N aqueous sodium hydroxideuntil basic. The resulting mixture was extracted with dichloromethane(2×). The combined organics were dried over magnesium sulfate, filteredand concentrated in vacuo to give the title compound (22 g, 78% yield).

(2R, 5S)-1-(4-Fluoro-benzyl)-2,5-dimethyl-piperazine

To a solution of (2R,5S)-1-(4-fluoro-benzyl)-3,6-dimethyl-piperazine-2,5-dione (22 g, 87.9mmol) in dry tetrahydrofuran (160 ml) at 0° C. was added a solution oflithium aluminum hydride (1M in tetrahydrofuran, 373 ml, 373 mmol)dropwise over 40 minutes. The reaction mixture was then refluxed for 4hours, cooled to ambient temperature and slowly quenched with water. Theresulting mixture was filtered through a pad of celite and the filtercake was washed with ethyl acetate. The filtrate was then concentrated,diluted with ethyl acetate and washed with saturated aqueous sodiumhydrogen carbonate. The organic layer was separated, dried overmagnesium sulfate, filtered and concentrated in vacuo to give the titlecompound (17.7 g, 91% yield).

(2R,5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of (2R, 5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine(2.5 g, 11.25 mmol) in dry dichloromethane (11 ml) at 0° C. was addedtriethylamine (1.57 ml, 11.2 mmol) followed by chloroacetyl chloride(0.858 ml, 11.2 mmol). The resulting reaction mixture was stirred for 30minutes. The reaction was then filtered through a pad of celite, washedwith dichloromethane and the resulting filtrate was concentrated to givea yellow oil Chromatography on silica get gave the title compound (2.84g, 86% yield).

(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoicacid methyl ester

To a solution of (2R,5S)-2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(2.75 g, 9.2 mmol) in butanone (50 ml) was added methyl5-chloro-2-hydroxybenzoate (1.55 g, 9.2 mmol), potassium carbonate (2.54g, 18.4 mmol) and potassium iodide (1.52 g, 9.2 mmol). The resultingmixture was stirred at reflux for 6 hours. The reaction was then cooled,diluted with ethyl acetate, and washed with brine. The organics weredried over magnesium sulfate, filtered and concentrated in vacuo to givean orange oil. Chromatography on silica gel gave the title compound (4.1g, 100% yield).

(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoicacid

To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoicacid methyl ester (4.12 g, 9.18 mmol) in tetrahydrofuran (10 ml),methanol (10 ml) and water (4 ml) was added lithium hydroxidemonohydrate (1.93 g, 45.9 mmol). The resulting mixture was stirredovernight at ambient temperature. The reaction was then concentrated,diluted with 1N hydrochloric acid and extracted with dichloromethane(2×). The organic layers were combined, dried over magnesium sulfate,filtered and concentrated to give a white foam. Triteration indichloromethane and diethyl ether gave the title compound (1.38 g, 35%yield).

(2R,5S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoicacid (0.10 g, 0.212 mmol) in dichloromethane (4 ml) was added4-dimethylaminopyridine (0.039 g, 0.318 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g,0.318 mmol) and tert-butyl 1-piperazinecarboxylate (0.041 g 0.222 mmol).The resulting mixture was stirred overnight at ambient temperature. Itwas then diluted with dichloromethane and washed with brine. Theorganics were dried over magnesium sulfate, filtered and concentrated togive a clear oil. Chromatography on silica gel gave the title compound(0.110 g, 85% yield).

(2R,5S)-2-[4-Chloro-2-(piperazine-1-carbonyl)-phenoxy]-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of (2R,5S)-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxylicacid tert-butyl ester (0.110 g, 0.182 mmol) in dichloroethane (10 ml)was added trifluoroacetic acid (5 ml). The reaction was stirred for twohours at ambient temperature. The reaction was then diluted withdichloromethane and washed with 1N aqueous sodium hydroxide. Theorganics were dried over magnesium sulfate, filtered and concentrated togive the title compound (0.080 g, 87% yield).

The title compounds for Examples 2-12 were prepared by a methodanalogous to that described in Example 1.

Example R²⁰ R² 2

Me 3

Me 4

H 5

H 6

H 7

H 8

H 9

H 10 —NHSO₂Me Me 11 —NH—(CH₂)₂—NHSO₂CH₃ CH₃ 12 —NH—(CH₂)₂—NHC(O)NH₂ CH₃

EXAMPLE 13

(2R)-3-Amino-N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]2-oxo-ethoxy}-phenyl)-propionamide

[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester

To a solution of2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone(0.066 g, 0.17 mmol) in methylene chloride (2 mL) at ambient temperaturewas added N-methylmorpholine (0.025 mL, 0.23 mmol),3-tert-butoxycarbonylamino-propionic acid (0.044 g, 0.23 mmol) andO-benzotriazole-1-yl-N,N,N′, N′-tetramethyluronium hexafluorophosphate(0.076 g, 0.20 mmol). The resulting solution was stirred at ambienttemperature for 60 hours, then concentrated. Radial chromatography (2 mmplate) gave the title compound (0.114 g)

(2R)-3-Amino-N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionamide

To a solution of[2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester (0.110 g, 0.2 mmol) in methylene chloride (3 mL)was added trifluoroacetic acid (0.50 mL). The reaction was stirred for 2hours at ambient temperature then diluted with saturated aqueous sodiumhydrogen carbonate. The mixture was extracted with methylene chlorideand the combined organics were dried over magnesium sulfate, filteredand concentrated in vacuo to give the title compound (0.069 g)

The title compounds for Examples 14-19 were prepared by a methodanalogous to that described in Example 13.

Example R²⁰ R² 14

H 15

H 16

H 17

H 18

H 19

H

EXAMPLE 20

(2R,5S)-2-(4-Chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoicacid methyl ester (1.0 g, 3.35 mmol) in butanone (35 ml) was added2-nitro-4-chlorophenol (0.639 g, 3.69 mmol), potassium carbonate (0.925g, 6.7 mmol) and potassium iodide (0.556 g, 3.35 mmol). The reactionmixture was heated at reflux overnight. The reaction mixture was thencooled, diluted with water and extracted with ethyl acetate. Thecombined organics were dried over magnesium sulfate, filtered andconcentrated to give an orange oil. Chromatography on silica gel gavethe title compound (1.35 g, 93% yield).

(2R,5S)-2-(2-Amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of (2R,5S)-2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(2.2 g, 5.05 mmol) in ethanol (50 ml) in a par bottle was added 5%platinum on carbon (2.2 g). The reaction mixture was subjected tohydrogen gas (35 psi) for thirty minutes. The reaction mixture wasfiltered through celite and washed with ethanol. The filtrate wasconcentrated to give a tan foam. Chromatography on silica gel gave thetitle compound (1.42 g, 70% yield).

(2R,5S)-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamicacid 4-nitro-phenyl ester

To a solution of (2R,5S)-2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(0.150 g, 0.37 mmol) in dichloromethane (7 ml) was added pyridine (0.066ml, 0.82 mmol) followed by 4-nitrophenyl chloroformate (0.075 g, 0.41mmol). The reaction was stirred at ambient temperature for 3½ hours. Thereaction mixture was concentrated followed by chromatography on silicagel to give the title compound (0.153 g, 74% yield).

(2R,5S)-1-(2-Amino-ethyl)-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-urea

To a solution of (2R,5S)-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamicacid 4-nitro-phenyl ester (0.206 g, 0.37 mmol) in dry methanol (6 ml)was added ethyldiamine (0.05 ml, 0.814 mmol). The reaction was stirredat ambient temperature overnight. The reaction was concentrated andchromatagraphed on silica gel to give the title compound (0.115 g, 63%yield).

The title compounds for Examples 21-27 were prepared by a methodanalogous to that described in Example 20.

Example R²⁰ R² 21

Me 22

H 23

Me 24

H 25

H 26

H 27

Me

EXAMPLE 28

(2R)-2-Amino-ethanesulfonic acid(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide

2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide

To a solution of of2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone(0.050 g, 0.13 mmol) in methylene chloride (1 mL) at ambient temperaturewas added triethylamine (0.027 mL, 0.19 mmol) and2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045g, 0.17 mmol). The reaction was stirred overnight at ambienttemperature. Additional triethylamine ((0.027 mL, 0.19 mmol) and2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.045g, 0.17 mmol) was added. The reaction was stirred one hour, thenadditional triethylamine (0.055 mL, 0.34 mmol) was added. The reactionwas stirred and hour, then additional2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.090g, 0.34 mmol) was added. After stirring an additional 1 hour, thereaction was treated with saturated aqueous sodium hydrogen carbonateand extracted with methylene chloride (3×). The combined organics weredried over magnesium sulfate, filtered and concentrated in vacuo.Purification via radial chromatography (2 mm plate) gave the titlecompound (0.030 g).

(2R)-2-Amino-ethanesulfonic acid(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide

To a solution of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonicacid(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide(0.030 g, 0.048 mmol) in EtOH (1 mL) at ambient temperature was addedhydrazine hydrate (0.025 mL). The reaction was stirred overnight atambient temperature then diluted with water and extracted with methylenechloride (2×). The combined organics were washed with saturated aqueousbrine and dried over sodium sulfate, filtered and concentrated in vacuo.Purification via radial chromatography (2 mm plate) gave the titlecompound (0.014 g).

The title compounds for Examples 29-34 were prepared by a methodanalogous to that described in Example 28.

Example R²⁰ R² 29 —SO₂CF₃ Me 30

H 31

H 32

H 33

H 34 —SO₂N(Me)₂ Me

EXAMPLE 35

(2R)-N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-cyanoguanidine

1-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-cyano-S-methyl-isothiourea

To a solution of of2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone(0.30 g, 0.77 mmol) in tetrahydrofuran (5 mL) at ambient temperature wasadded sodium hydride (0.029 g, 1.22 mmol) and the reaction was stirredfor 30 minutes. To this was added S,S1-dimethyl N-cyanodithioiminocarbonate (0.168, 1.15 mmol) and the mixture was heated at refluxovernight. The reaction was cooled and quenched with saturated aqueousammonium chloride. The mixture was extracted with EtOAc and the combinedorganics were dried over Na₂SO₄, filtered and concentrated in vacuo.Chromatography on silica gel gave the title compound (0.350 g)

(2R)-N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-cyanoguanidine

To a solution of1-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-cyano-S-methyl-isothiourea(0.045 g, 0.092 mmol) in EtOH (1 mL) was added ammonium hydroxide (0.100mL) and the resulting solution was shaken at 60° C. overnight. The crudereaction mixture was purified directly via radial chromatography (2 mmplate) to give the title compound (0.027 g).

The title compounds for Examples 36-38 were prepared by a methodanalogous to that described in Example 35.

Example R²⁰ R² 36

H 37

H 38

H

EXAMPLE 39

(2R,5S)-2-{4-Chloro-2-[(2-diethylamino-ethylamino)-methyl]-phenoxy}-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde

To a solution of2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(2.87 g, 9.6 mmol) in DMF (20 mL) was added 5-chlorosalicylaldehyde(1.65 g, 10.5 mmol), potassium carbonate (2.64 g, 19.2 mmol) andpotassium iodide (1.59 g, 9.6 mmol). The resulting mixture was heated to100° C. for 12 hours. The reaction was cooled, diluted with saturatedaqueous brine and extracted with ethyl acetate (3×). The combinedorganics were dried over magnesium sulfate and filtered. The filtratewas concentrated in vacuo to give crude product. Purification viachromatography on silica gel (15% EtOAc/Hexanes) gave the title compound3.40 g, 85% yield.)

(2R,5S)-2-{4-Chloro-2-[(2-diethylamino-ethylamino)-methyl]-phenoxy}-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde(0.100 g, 0.25 mmol) in 10:1 dichloroethane acetic acid (2.2 mL) wasadded (diethylamino)ethylamine (0.088 mL, 0.625 mmol) and the resultingsolution was stirred for 1 hour at ambient temperature. To this wasadded sodium cyanoborohydride (0.0094 g, 0.15 mmol) and the reaction wasstirred overnight at ambient temperature. Upon completion water wasadded and the mixture was basified with solid sodium bicarbonate(pH>10). The product was extracted with dichloromethane (2×) and diethylether (2×). The combined organics were dried over magnesium sulfate,filtered and concentrated in vacuo. Chromatography on silica gel gavethe title compound (0.039 g, x 30% yield)

The title compounds for Examples 40-62 were prepared by a methodanalogous to that described in Example 39.

Example R²⁰ R² 40

Me 41

Me 42

Me 43

Me 44

Me 45

Me 46

Me 47

Me 48

Me 49

Me 50

Me 51

Me 52

Me 53

Me 54

Me 55

Me 56

Me 57

Me 58

Me 59

Me 60

Me 61

Me 62

Me

EXAMPLE 63

N(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-2-diethylamino-acetamide

(2R,5S)-2-(2-Aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone

To a solution of(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde(1.86 g, 4.44 mmol) in MeOH (20 mL) was added ammonium acetate (3.42 g,44 mmol) and sodium cyanoborohydride (0.195 g, 3.1 mmol). The resultingmixture was stirred overnight at ambient temperature. The reaction wasquenched with concentrated hydrochloric acid and concentrated in vacuo.The residue was dissolved in water and basified with aqueous 3N NaOH(pH>10). The product was extracted with dichloromethane (2×) and ethylacetate (2×). The combined organics were dried over magnesium sulfate,filtered and concentrated in vacuo. Chromatography on silica gel gavethe title compound (1.29 g, 69% yield)

N-(5-Chloro-2-(2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy)-benzyl)-2-diethylamino-acetamide

To a solution of N,N-dimethylglycine (0.014 g, 0.13 mmol) and(2R,5S)-2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(0.063 g, 0.15 mmol) in dichloromethane (2 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.034 g, 0.18 mmol),1-hydroxybenzotriazole (0.021 g, 0.15 mmol), and triethylamine (0.036mL, 0.36 mmol). After the reaction was stirred for 48 hours, thesolution was diluted with saturated aqueous sodium bicarbonate andextracted with dichloromethane (3×). The combined organics were driedover magnesium sulfate, filtered and concentrated in vacuo.Chromatography on silica gel gave the title compound (0.063 g, 80%).

The title compounds for Examples 64-85 were prepared by a methodanalogous to that described in Example 63.

Example R²⁰ R² 64

Me 65

Me 66

Me 67

Me 68

Me 69

Me 70

Me 71

Me 72

Me 73

Me 74

Me 75

Me 76

Me 77

Me 78

H 79

H 80

Me 81

Me 82

Me 83

Me 84

H 85

H

EXAMPLE 86

(2R,5S)-(N-{2-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-ureido]-ethyl}-acetamide

To a solution of(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamine(0.200 g, 0.477 mmol) in methylene chloride (10 mL) was added pyridine(0.077 mL, 0.954 mmol) and 4-nitro phenyl chloroformate (0.097 g, 0.525mmol). The resulting mixture was stirred for one hour at ambienttemperature and then concentrated in vacuo. The residue (0.055 g, 0.094mmol) was dissolved in methanol (1 mL). N-Acetylethylenediamine (0.019mL, 0.188 mmol) was added and the reaction was stirred at roomtemperature over night. The reaction was concentrated in vacuo andchromatography on silica gel gave the title compound (0.019 g, 27%).

The title compounds for Examples 87-90 were prepared by a methodanalogous to that described in Example 86.

Example R²⁰ R² 87

Me 88

Me 89

Me 90

Me

EXAMPLE 91

(2R,5S)-2-Amino-ethanesulfonic acid5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide

(2R,5S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide

To a solution of(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamine (0.060 g, 0.143 mmol) in methylene chloride (3 mL) was added2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.043g, 0.150 mmol) and triethylamine (0.060 mL, 0.43 mmol) and the solutionwas stirred 1 hr at ambient temperature. The reaction was diluted withsaturated aqueous sodium hydrogen carbonate and extracted with methylenechloride. The combined organics were dried over magnesium sulfate,filtered and concentrated in vacuo. Chromatography on silica gel gavethe title compound (0.073 g, 77%).

(2R,5S)-2-Amino-ethanesulfonic acid5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide

To a solution of(2R,5S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide(0.073 g, 0.111 mmol) in EtOH (1 mL) was added hydrazine (35% aq. 0.25mL, 2.73 mmol) and the solution was stirred overnight at ambienttemperature. The reaction was filtered through a glass frit and washedwith EtOH. The filtrate was concentrated in vacuo to give the titlecompound (0.056 g, 96%)

The title compounds for Examples 92-93 were prepared by a methodanalogous to that described in Example 91.

Example R²⁰ R² 92

H 93 —SO₂NMe₂ Me

EXAMPLE 94

(2R)-N-(2-Amino-ethyl)-N′-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-cyanoguanidine

A solution of2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-ethanone(0.025 g, 0.062 mmol) and diphenyl cyanocarbonimidate (0.016 g, 0.068mmol) in ethanol (1 mL) was heated on a shaker plate at 60° C. After 22h, ethylenediamine (0.008 mL, 0.123 mmol) was added and the resultingsolution was heated on a shaker plate at 60° C. for an additional 21 h.The solution was cooled to ambient temperature, concentrated andpurified using radial chromatography to yield the title compound (0.021g, 67%). The title compounds for Examples 95-96 were prepared by amethod analogous to that described in Example 94.

Example R²⁰ R² 95

H 96

H

EXAMPLE 97

(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-N-methyl-benzenesulfonamide

5-Chloro-2-methoxy-N-methyl-benzenesulfonamide

To a solution of 5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g,4.15 mmol) in tetrahydrofuran(8 ml) was bubbled methylamine gas untilsaturated. The reaction mixture was sealed with a septa and stirredovernight at ambient temperature. The reaction mixture was thenconcentrated, triterated in dichloromethane and ether, filtered anddried yielding the above titled compound 1.05 g (>100%) white solid.

5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide

To a solution of sodium hydride (60% in mineral oil, 90.24 mg, 2.25mmol) in dry dimethyl formamide was added thiophenol (0.225 ml, 2.25mmol) dropwise. To this was then added5-Chloro-2-methoxy-N-methyl-benzenesulfonamide (531 mg, 2.25 mmol)followed by refluxing for 4 hours. The reaction mixture was cooled,diluted with ethyl acetate and washed with a 1N sulfuric acid solution.The organic layer was separated, dried over magnesium sulfate, filteredand concentrated in vacuo. Chromatography on silica gel yielded theabove titled compound (320 mg, 53% yield).

(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-N-methyl-benzenesulfonamide

To a solution of (2R,5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone(375 mg, 1.26 mmol) in butanone (12 ml) was added5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide (280 mg, 1.26 mmol),potassium carbonate (348 mg, 2.52 mmol) and potassium iodide (209 mg,1.26 mmol). The resulting reaction mixture was refluxed for 4 hours. Itwas allowed to cool, diluted with ethyl acetate and washed with brine.The organic layer was separated, dried over magnesium sulfate, filteredand concentrated in vacuo. Chromatography on silica gel gave the abovetitled compound (320 mg, 53% yield).

The title compounds for Examples 98-100 were prepared by a methodanalogous to that described in Example 97.

Example R²⁰ R² 98 —NH₂ Me 99

Me 100

Me

What is claimed is:
 1. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R²⁰ and R² areas defined below: R²⁰ R²

H

Me

H

H

H —SO₂N(Me)₂ Me.


2. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R²⁰ and R² areas defined below: R²⁰ R²

H

H

H

H.


3. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R²⁰ and R² areas defined below: R²⁰ R²

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me.


4. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R²⁰ and R² areas defined below: R²⁰ R²

H —SO₂NMe₂ Me.


5. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R² is H and R²⁰is

or


6. A pharmaceutical composition for treating or preventing a disorder orcondition that can be treated or prevented by inhibiting chemokinebinding to the receptor CCR1 in a mammal, comprising an amount of acompound according to any of claims, 1, 2, 3, 4, 5, or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and a pharmaceutically acceptablecarrier.